Fenvalerate exhibits no effect on PP2B-Bβ [1].

Absorption, Distribution and Excretion
Metabolism and bioaccumulation of fenvalerate and its fenvalerate its metabolites in liver, kidney and brain of rat following the oral administration of a sub-lethal dose (15 mg/kg) of the pesticide for 7, 15 and 30 day periods was investigated by high-performance liquid chromatography (HPLC) in terms of the relative mole concentrations in rat tissues. The cleavage of the ester linkage in fenvalerate yielding two metabolites was found to be primary step in the biodegradation of fenvalerate in rat organs. These metabolites were purified to homogeneity by HPLC and characterized by infra-red spectroscopy as 4-chloro-alpha-(1-methylethyl) benzeneacetic acid and 3-phenoxy benzoic acid.
The disposition kinetics of fenvalerate were studied in goats after dermal application of 100 mL of 0.25% (w/v) solution. The insecticide persisted in the blood for 72 hr. The mean (+/- SEM) Vd(area) and apparent t 1/2 (beta) were 9.92 +/- 1.44 L/kg and 17.51 +/- 2.65 hr, while the AUC and ClB values were respectively 82.15 +/- 7.40 ug hr/mL and 0.56 +/- 0.05 L/(kg hr). Four days after the dermal application, the highest concentration of fenvalerate residues was found in the adrenal gland, followed by the biceps muscle, omental fat, liver, kidney, lung and cerebrum in that order. Fenvalerate caused hyperglycaemia but had no effect on serum protein and cholesterol levels. Serum acetylcholinesterase activities were increased after 24 hr but were below the initial values from 48 to 120 hr.
Poorly absorbed through rabbit skin.
Elimination from body fat is slow, with a half-life of 7-10 days; elimination from brain is less slow, with a half-life of 2 days, presumably due to the more effective perfusion of brain and the presence of esterases in brain tissue.
For more Absorption, Distribution and Excretion (Complete) data for FENVALERATE (21 total), please visit the HSDB record page.

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Metabolism / Metabolites
Fenvalerate undergoes hydroxylation to give 2'- or 4'- hydroxylated phenoxy esters and hydrolysis to give 3-phenoxybenzoic acid and its hydroxy derivatives (free and conjugates), 3-(4-chlorophenyl)-isovaleric acid and its hydroxy derivatives (free, lactones, and conjugates), thiocyanate, and CO2.
The fate of fenvalerate in rats and mice has been studied using fenvalerate radiolabelled in the acid moiety or benzyl or cyano groups. The administered radioactivity, except that of the cyano-labelled compounds, is readily excreted (up to 99% in 6 days). The major metabolic reactions are ester cleavage and hydroxylation at the 4' position. Various oxidative and conjugation reactions that lead to a complex mixture of products have been shown to occur. When studies were carried out with fenvalerate radiolabelled in the cyano group, elimination of the radioactive dose was less rapid (up to 81% in 6 days). The remaining radioactivity was retained mainly in the skin, hair, and stomach as thiocyanate. A minor, but very important, metabolic pathway is the formation of a lipophilic conjugate of (2R)-2-(4-chlorophenyl)isovalerate. This congugate, which is implicated in the formation of granuloma, has been detected in the adrenals, liver mesenteric lymph nodes of rats, mice, and some other species.
Despite its lack of a cyclopropane ring in the acid, fenvalerate is rapidly metabolized in rats by ester cleavage and hydroxylation, as are the more traditional pyrethroids.
On a single oral dose or five consecutive oral doses of (14)C-esfenvalerate or (14)C-fenvalerate labeled in the acid moiety to 13-day pregnant rats at rates of 2.5 and 10 mg/kg/day, respectively, the maternal blood and placenta generally showed higher (14)C levels as compared with the fetus and amniotic fluid. Both compounds and their metabolites did not transfer readily from the maternal blood to the fetus, the amount of (14)C transferred being less than 0.07% of the dose. There were no substantial differences in the fetal (14)C level and the transfer ratio ((14)C tissue level/(14)C maternal blood level) between both labeled preparations. Major (14)C-compounds in the fetus, maternal blood and placenta were the parent compounds, CPIA (2-(4-chlorophenyl)isovaleric acid) and CPIA-hydroxylated derivatives and there was no qualitative difference in metabolic fates between the two compounds, except that a trace amount of CPIA-cholesterol ester (cholesteryl (2R)-2-(4-chlorophenyl)isovalerate] was detected in the maternal blood and placenta only with fenvalerate. CPIA-cholesterol ester did not seem to transfer from the maternal blood to the fetus. Overall, esfenvalerate and fenvalerate seem to behave in the same manner as far as placental transfer was concerned.
For more Metabolism/Metabolites (Complete) data for FENVALERATE (23 total), please visit the HSDB record page.
Esfenvalerate has known human metabolites that include 4'-hydroxy-esfenvalerate and 2'-hydroxy-esfenvalerate.
Following ingestion, pyrethriods are hydrolysed by various digestive enzymes in the gastro-intestinal tract. However, a small portion of the insecticidally active compounds or its derivatives are absorbed, as shown by their toxicity and their effect on the liver. Pyrethriods may also be absorbed following inhalation or dermal contact. They are rapidly distributed to most tissues, particularly to those with a high lipid content, and are concentrated in central and peripheral nervous tissues. Pyrethriods or their metabolites are not known to be stored in the body or to be excreted in the milk, but no study of the matter has employed modern methods. The major metabolic pathways for pyrethriods are hydrolysis of the central ester bond, oxidative attacks at several sites, and conjugation reactions, to produce a complex array of primary and secondary water-soluble metabolites that undergo urinary excretion. Metabolism is believed to involve nonspecific microsomal carboxyesterases and microsomal mixed function oxidases, which are located in nearly all tissue types, with particularly high activities in the liver. Metabolites are excreted in the urine and faeces. (L857, L889)

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Biological Half-Life
When carp (Cyprinus carpio) was exposed to ((14)C-CN)-(2S, alphaRS)-fenvalerate (0.8 ug/litre) under semi-static conditions for 7 days, the radioactivity in fish increased to a level of 922 ug/kg. Once the fish were transferred to fresh water, the levels of radioactivity in the fish decreased with an initial half-life of 5 days ... . /(2S, alphaRS)-Fenvalerate/
Elimination from body fat is slow, with a half-life of 7-10 days; elimination from brain is less slow, with a half-life of 2 days (Marei et al., 1982), presumably due to the more effective perfusion of brain and the presence of esterases in brain tissue.
Metabolism in dogs was studied with ((14)C-chlorophenyl)- or ((14)C-phenoxybenzyl)-fenvalerate administered as a single oral dose of 1.7 mg/kg bw, dissolved in corn oil, in gelatine capsules. Excreta and blood were collected daily for 3 days and analysed for radioactivity by liquid scintillation counting. ... More total radioactivity was recovered in animals given ((14)C-chlorophenyl)-fenvalerate than in those given ((14)C-phenoxybenzyl)-fenvalerate, and the half-lives were 1 day and 0.7 day, respectively. ...

Toxicity Summary
Both type I and type II pyrethroids exert their effect by prolonging the open phase of the sodium channel gates when a nerve cell is excited. They appear to bind to the membrane lipid phase in the immediate vicinity of the sodium channel, thus modifying the channel kinetics. This blocks the closing of the sodium gates in the nerves, and thus prolongs the return of the membrane potential to its resting state. The repetitive (sensory, motor) neuronal discharge and a prolonged negative afterpotential produces effects quite similar to those produced by DDT, leading to hyperactivity of the nervous system which can result in paralysis and/or death. Other mechanisms of action of pyrethroids include antagonism of gamma-aminobutyric acid (GABA)-mediated inhibition, modulation of nicotinic cholinergic transmission, enhancement of noradrenaline release, and actions on calcium ions. They also inhibit calium channels and Ca2+, Mg2+-ATPase. (T10, T18, L857)

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Toxicity Data
LD50: 70.2 mg/kg (Oral, Rat) (T13)

LD50: 2500 mg/kg (Dermal, Rabbit) (T13)

LD50: 340 mg/kg (Intraperitoneal, Rat) (T92)

LD50: 65 mg/kg (Intravenous, Mouse) (T92)

LC50: >101 g/m3 over 4 hours (Inhalation, Rat) (T93)

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Interactions
Fenvalerate, a widely used pesticide, was administered orally to goats at a dose rate of 15 mg/kg body weight, daily for 270 days. After 90 days of dosing, the animals, together with appropriate controls, were vaccinated with Brucella abortus strain 19. The fenvalerate reduced both the humoral and cell-mediated immune responses, as assessed by the standard tube agglutination test and delayed hypersensitivity test, respectively.
The ability of 3 mg/kg/day diazepam to alter the neurobehavioral and neurochemical consequences of perinatal exposure to Ambush and Pydrin was examined. Seventy-two pregnant female rats served as subjects. Half of the subjects were treated with diazepam and the other half were treated with the vehicle via subcutaneous osmotic pumps for 33 days starting on gestational day 1 Each group was further divided into six gavage treatment groups: corn oil, corn oil + 96% xylene, 1.25 or 0.125 mg/kg Pydrin, and 4.0 or 0.4 mg/kg Ambush. Behavioral evaluations were conducted on half the pups in each litter and the other pups were used for the neurochemical assays. Behavioral evaluations included locomotor activity, screen testing, and passive avoidance learning. Brains for neurochemical analysis were extracted and sectioned into frontal cortex, caudate, hippocampus and cerebellum. Neurochemical assays assessed levels of DA, DOPAC, 5-HIAA, 5-HT, HVA, aspartate, glutamate, glutamine, glycine, GABA, and taurine. Diazepam treatment did produce some neurotoxicity in the control pups but diazepam exposure did reverse elevations in amino acid levels in the cerebellum produced by both pyrethroids. In addition diazepam reversed the pyrethroid effects on activity and muscular coordination. These diazepam effects were not specific to Type I or Type II pyrethroids.
This investigation explored the behavioral and neurochemical toxicity of perinatal oral exposure to Ambush (Type I) and Pydrin (Type II), two pyrethroid formulations. Thirty-six female rats were mated and exposed to various pyrethroid formulations by oral gavage from the first gestational day until their pups (culled to 8/litter) were 12 days old. Six mothers were exposed daily to one of the following treatments: corn oil control, corn oil+96% xylene, 1.25 mg/kg Pydrin (pesticidal ingredient fenvalerate), 0.125 mg/kg Pydrin, 4.0 mg/kg Ambush (pesticidal ingredient permethrin), or 0.4 mg/kg Ambush. Behavioral evaluations of locomotor activity, muscular coordination and passive avoidanc learning were conducted on half of the pups from each litter (N = 24 pups/treatment condition). The other pups were sacrificed, brains were removed and sectioned into frontal cortex, hippocampus, caudate, and cerebellum for neurochemical assessment. The monoamines DA, DOPAC, 5-HIAA, 5-HT and HVA levels were determined and the amino acids aspartate, glutamate, glutamine, glycine, GABA, and taurine were determined for each of the brain regions. Gestational duration was shortened by exposure to the high doses of Pydrin and Ambush but only pups from the 4.0 mg/kg Ambush group were significantly lighter. No physical malformations were observed in pups from any of the treatment conditions, although the high Pydrin exposure condition resulted in a 4% death rate. Behavioral changes were seen for both locomotor activity and muscular coordination. The shape of across-session habituation of locomotion was different for the xylene and corn oil and the high dose Ambush groups. Both groups were less active on day 1 and more active on days 2 and 3 than the other pups. The high doses of Ambush and Pydrin produced slower intrasession habituation. Muscular coordination was improved slightly following low dose exposure to both pesticides and reduced following high dose exposures. Regional brain weights were normal for the cortex, cerebellum and caudate but the hippocampus was 64% heavier for pups treated with 4.0 mg/kg Ambush. Amino acid determinations indicated that the cerebellum was most affected where glutamate, glutamine, aspartate and taurine were reduced following xylene or pyrethroid exposure. The biogenic amine transmitter 5-HT was reduced in several brain regions following pyrethroid exposures. These data suggest that levels of Ambush and Pydrin as low as the LD50/10,000 can alter behavior and neurotransmitter functioning.
Following the administration of a single or repeated doses of dimethoate, carbaryl, and fenvalerate, the activities of tryptophan-2,3-dioxygenase, indoleamine-2,3-dioxygenase, kynurenine, kynureninase, kynurenine-transaminase, and pyridoxal-phosphokinase were determined in the liver, kidney and lung of male Wistar rats. Treatment consisted of 10% of the median lethal dose of each insecticide given orally for the single dosing investigations and 5% of the median lethal dose was given orally for 5 consecutive days as repeated doses. Weight losses in both body and organ were noted only after repeated dose of dimethoate. Significant decreases in the activity of kynurenine-3-hydroxylase, kynurenine-2-oxoglutarate-transaminase, kynurenine-pyruvate-transaminase, and pyridoxal-phosphokinase were noted following repeated administration of dimethoate. Carbaryl in repeated doses caused significant decreases in the activity of apo-tryptophan-2,3-dioxygenase, kynurenine-2-oxoglutarate-transaminase, kynurenine-pyruvate-transaminase, and serine-glyoxylate-transaminase. An inhibition was noted in tryptophan-2,3-dioxygenase following external addition of insecticides at different concn to an incubation mixture. Other enzymes demonstrated no change in their activities following this treatment.
For more Interactions (Complete) data for FENVALERATE (14 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 451 mg/kg
LD50 Rat percutaneous > 5000 mg/kg
LD50 Rat oral 3200 mg/kg /technical pydrin suspended in water/
LD50 Rat oral 1-3 g/kg /technical grade/
For more Non-Human Toxicity Values (Complete) data for FENVALERATE (29 total), please visit the HSDB record page.

[1]. Specific Inhibition of Calcineurin by Type II Synthetic Pyrethroid Insecticides. Biochem Pharmacol. 1992 Apr 15;43(8):1777-84.

[2]. Regulation of Organelle Movement in Melanophores by Protein Kinase A (PKA), Protein Kinase C (PKC), and Protein Phosphatase 2A (PP2A). J Cell Biol. 1998 Aug 10;142(3):803-13.

Therapeutic Uses
MEDICATION (VET): ectoparasiticide
/VET:/ Louse control requires treatment with an effective insecticide or drug ... . A few compounds may be applied as a whole-body spray for lice control. A light, mist application of some formulations may be effective, while others may require soaking the hair to the skin. ... Both swine and sheep may be sprayed with fenvalerate. A low-volume spray of fenvalerate is approved for sheep and nonlactating goats. ... Fenvalerate pour-on is approved for louse control on swine, sheep, and nonlactating goats.

C25H22CLNO3

419.905

419.128

51630-58-1

Fenvalerate-d5;1246815-00-8;Fenvalerate-d6;82523-66-8

3347

Off-white to light yellow solid powder

1.2±0.1 g/cm3

538.9±50.0 °C at 760 mmHg

39.5 - 53.7 °C

279.7±30.1 °C

0.0±1.4 mmHg at 25°C

1.586

6.68

0

4

8

30

586

0

NYPJDWWKZLNGGM-UHFFFAOYSA-N

InChI=1S/C25H22ClNO3/c1-17(2)24(18-11-13-20(26)14-12-18)25(28)30-23(16-27)19-7-6-10-22(15-19)29-21-8-4-3-5-9-21/h3-15,17,23-24H,1-2H3

[cyano-(3-phenoxyphenyl)methyl] 2-(4-chlorophenyl)-3-methylbutanoate

Evercide 2362; Fenvalerate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~238.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)